Modern anti-seizure drug development yielded benefits in terms of improved pharmacokinetics, safety and tolerability profiles, but offered no advances in efficacy compared to previous older generations of anti-seizure drugs. Despite significant advances in our understanding of the genetic bases to epilepsy, and a welcome renewed interest on the severe monogenic epilepsies, modern genetics has yet to directly inform more effective or disease-modifying anti-seizure drugs. Here, we describe a new approach to the identification of novel disease modifying anti-epilepsy drugs. The systems genetics approach aims to first identify pathophysiological mechanisms by integrating polygenic risk with cellular gene expression profiles and then to relate these molecular mechanisms to druggable targets using a gene regulatory (regulome) framework. The approach offers an exciting and flexible framework for future drug discovery in epilepsy, and is applicable to any disease for which appropriate cell-type and disease-context specific data exist. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.

中文翻译：

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抗癫痫药发现的系统级框架。

现代抗癫痫药的开发在改善药代动力学，安全性和耐受性方面带来了好处，但与以前的较早几代抗癫痫药相比，其疗效没有任何提高。尽管我们对癫痫病遗传基础的理解有了长足的进步，并且人们对严重的单基因癫痫病重新产生了兴趣，但现代遗传学尚未直接为更有效或可改变疾病的抗癫痫药提供信息。在这里，我们描述了一种新的方法来识别新型疾病修饰抗癫痫药。系统遗传学方法的目的是首先通过将多基因风险与细胞基因表达谱相整合来确定病理生理机制，然后使用基因调控（regulome）框架将这些分子机制与可治疗靶标相关联。该方法为癫痫病的未来药物发现提供了令人兴奋且灵活的框架，并且适用于存在适当细胞类型和特定疾病背景数据的任何疾病。本文是名为“ 21世纪的新癫痫疗法-从抗癫痫药到预防，改良和治疗癫痫病”的特刊的一部分。